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Antimicrobial Agents and Chemotherapy, August 1999, p. 1895-1900, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

In Vitro and In Vivo Activities of Syn2190, a Novel beta -Lactamase Inhibitor

Kouichi Nishida,1,* Chieko Kunugita,1 Tatsuya Uji,1 Fusahiro Higashitani,1 Akio Hyodo,1 Norio Unemi,1 Samarendra N. Maiti,2 Oludotun A. Phillips,2 Paul Spevak,2 Kevin P. Atchison,2 Sameeh M. Salama,2 Harninder Atwal,2 and Ronald G. Micetich2

Antimicrobial Research Laboratory, Taiho Pharmaceutical Co., Ltd. Tokushima 771-0194, Japan,1 and SynPhar Laboratories Inc., Edmonton, Alberta T6E 5V2, Canada2

Received 19 October 1998/Returned for modification 10 February 1999/Accepted 20 May 1999

Syn2190, a monobactam derivative containing 1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor of group 1 beta -lactamase. The concentrations of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% for Syn2190 against these enzymes were in the range of 0.002 to 0.01 µM. These values were 220- to 850-fold lower than those of tazobactam. Syn2190 showed in vitro synergy with ceftazidime and cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1 beta -lactamase-producing strains, such as Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Morganella morganii. However, against beta -lactamase-derepressed mutants of P. aeruginosa, the MICs of ceftazidime plus Syn2190 were not affected by the amount of beta -lactamase, and the values were the same for the parent strains. The MICs at which 50% of isolates are inhibited (MIC50s) of ceftazidime plus Syn2190 were 2- to 16-fold lower than those of ceftazidime alone for ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC50s of cefpirome plus Syn2190 were two- to eightfold lower for cefpirome-resistant clinical isolates. The synergies of Syn2190 plus ceftazidime or cefpirome observed in vitro were also reflected in vivo. Syn2190 improved the efficacies of both cephalosporins in both a murine systemic infection model with cephalosporin-resistant rods and urinary tract infection models with cephalosporin-resistant P. aeruginosa.

* Corresponding author. Mailing address: Antimicrobial Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno Hiraishi Kawauchi-cho, Tokushima 771-0194, Japan. Phone: 088-665-5327. Fax: 088-665-6554.

Antimicrobial Agents and Chemotherapy, August 1999, p. 1895-1900, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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